WO2015097679A1

WO2015097679A1 - Ablation device and method for subsurface biological tissue ablation

Info

Publication number: WO2015097679A1
Application number: PCT/IB2014/067308
Authority: WO
Inventors: Demetri Psaltis; Jae-Woo Choi; Thomas LANVIN; Alexandre GOY
Original assignee: Ecole Polytechnique Federale De Lausanne (Epfl)
Priority date: 2013-12-24
Filing date: 2014-12-24
Publication date: 2015-07-02

Abstract

The present invention relates to a subsurface laser-induced optical breakdown (LIOB) ablation system including an optical source for providing optical pulses and an optical waveguide for guiding the optical pulses to a subsurface target biological tissue site. The system is characterised in that it further includes a pulse shaping system configured to modify a temporal profile or a wavefront profile of an optical pulse provided by the optical source to compensate for temporal or spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site, and configured to provide the compensated optical pulse to the optical waveguide for guidance to the subsurface target biological tissue site. The present invention also relates to a catheter and a subsurface laser-induced optical breakdown (LIOB) ablation method.

Description

Ablation device and method for subsurface biological tissue ablation

TECHNICAL FIELD OF THE INVENTION: The present invention relates to an ablation device and method and in particular to a device and method for performing lowly invasive ablation of targeted tissues (e.g atherosclerotic plaques, renal nerves, cancer tumors), via for example a catheter, at high ablation energy peak power without damaging the healthy tissues between the target tissue and the catheter. Several possible embodiments of the invention will be presented. Figures 0(a) to 0(c) illustrate a general representation of the invention.

In particular, the ablation of the present invention concerns laser-induced optical breakdown (LIOB) ablation. Ablation being the removal or destruction of a body part or biological tissue using the energy of a laser pulse.

BACKGROUND OF THE INVENTION:

LIOB ablation has been used in a free space optical configuration (see "Sub-Surface, Micrometer-Scale Incisions Produced in Rodent Cortex using Tightly-Focused Femtosecond Laser Pulses", J. Nguyen et al., 2012, Lasers in Surgery and Medicine). However, such a configuration does not permit LIOB to be carried out in-vivo inside a body, for example, in arteries.

As opposed to the catheters for removing plaques currently known (see, for example, Patent US 6673064), the present invention has a main advantage in that it allows the use of ultrashort (less than 1000 picosecond, preferably less than 100 picosecond and most preferably less than 10 picosecond) high energy (>0.1μΓ) pulses for ablation. When correctly focused at a target area, these pulses produce an ablation mechanism fundamentally different from absorption ablation. Known in-vivo ablation methods (see for example, "Endovenous Laser Ablation-Induced Complications: Review of the Literature and New Cases », RR Van Den Bos et al., 2009, Dermatologic Surgery) not only damage tissue at the target site but also damage surrounding tissue outside of the target site. This is particularly problematic in regions close to vital organs such as the heart or the brain where fragments of damaged tissue can subsequently enter the blood stream if outer tissue walls are damaged or removed during the ablation process.

None of the existing techniques efficiently allows for subsurface ablation of plaque without significant destruction of the upper healthy tissues. While some existing patents or patent applications (see for example US 8617148 or US 2009/0198223) disclose carrying out LIOB ablation in arteries via a catheter, the present invention reaches peak intensities (in the order of a terawatt per square cm) at the targeted area which are not currently possible and without significant intermediate tissue damage.

SUMMARY OF THE INVENTION:

Figure 0 presents in a general manner the present invention in relation to subsurface ablation of biological tissue. In Figure 0(a), a laser produces an optical pulse which is shaped by a pulse- shaping system, and then transmitted to the target ablation site inside a patient via an optical fiber catheter. Figure 0(b) illustrates a close-up of the output of the catheter, for example for ablating through arterial walls (where 1 is an optical fiber, 2 is a focusing system, 3 is a laser beam focused on a target, 4 is an area to be ablated (for example: an atherosclerotic plaque), 5is a lumen of the artery, 6 is a first layer of the arterial wall (endothelium)).

The system and method of the present invention advantageously permits peak light intensity values (in the order of a terawatt per square cm) to be reached at the targeted area 4 which are currently not reachable. Figure 0(c) represents schematically the ablation beam from the catheter output to the target site, where we want to reach the highest possible light intensity to eliminate unhealthy tissue while maintaining low light intensity at the surface of the sample, to limit damage to healthy tissue surrounding the target area or upstream of the target area. The system and method of the present invention advantageously not only permits peak light intensity values (in the order of a terawatt per square cm) to be reached at the targeted area 4 which are currently not reachable but additionally permits improved confinement of the ablated area in order to significantly limit or eliminate any damage to healthy tissue. The ablation mechanism is laser-induced optical breakdown (LIOB) ablation.

In LIOB ablation, a high number of photons reach a target area at the same time, and during this very short time the very high light intensity present at the target area allows for electrons to be detached from their atoms, thus creating a plasma in the target material or tissue. The apparition of this plasma can come with the creation of a bubble, the creation of a Shockwave and the short-scale release of reactive species, that is, different phenomena which can induce damage in the surrounding medium.

The main advantage of the LIOB ablation technique over absorption ablation is that in the case of LIOB, extremely high light intensities are present at the target spot creating a plasma of very small (less than ΙΟμιη) size in the axis of the laser beam, while absorption ablation in contrast damages the sample in a range of tens of micrometers.

Another advantage of LIOB is that, as opposed to absorption ablation, it does not depend on the absorption parameters of the target area. As previously mentioned, known methods not only damage tissue at the target site but also damage surrounding tissue outside of the target site. This is particularly problematic in regions close to vital organs such as the heart or the brain where fragments of damaged tissue can subsequently enter the blood stream if outer tissue walls are damaged or removed during the ablation process. The LIOB system and method according to the present invention allows damaging of a target area without damaging the upper layers of healthy tissue sample. This has direct applications for the ablation of plaque in arteries, where none of the existing techniques efficiently allows for subsurface ablation of the plaque without destroying the upper healthy tissues. It can also be used in the ablation of neurons close to the artery walls, by coming from the inside of the artery with an endoscope, as well as in biology and medicine.

The present invention reaches peak intensities (in the order of a terawatt per square cm) at the targeted area which are not currently possible and without intermediate tissue damage now possible thanks to the use of the particular pulse shaping techniques of the present invention. Reaching higher peak intensity in such a way does not only allow the ablation process to be more efficient, but it also allows it to be significantly more practical and, most importantly, it allows LIOB ablation at depths (greater than 50 micrometers) which would otherwise not be possible to reach through an optical fiber.

To overcome the above mentioned problems, the present invention relates to a subsurface laser- induced optical breakdown (LIOB) ablation system according to claim 1, a catheter according to claim 22 and a subsurface laser-induced optical breakdown (LIOB) ablation method according to claim 23.

BRIEF DESCRIPTION OF THE FIGURES:

The above object, features and other advantages of the present invention will be best understood from the following detailed description in conjunction with the accompanying drawings, in which:

Figure 0(a), 0(b) and 0(c) illustrate an optical system and method according to the present invention; Figure 1 illustrates an optical system according to an embodiment of the present invention; Figure 2 illustrates an optical system according to a further embodiment of the present invention; Figure 3(a) illustrates an optical system according to another embodiment of the present invention;

Figure 3(b) illustrates an exemplary system of the present invention; Figure 3(c) illustrates temporal pulse pre-shaping for a simple case of dispersion, where the vertical axis represents the measured power, and the horizontal axis represents time;

Figure 3(d) illustrates an exemplary holographic recording system of the present invention; Figure 4 illustrates an optical system according to a further embodiment of the present invention;

Figure 5 illustrates an optical system according to another embodiment of the present invention;

Figure 6(a) illustrates an optical system according to another embodiment of the present invention;

Figure 6(b) illustrates an exemplary implementation of the embodiment of Figure 6(a);

Figure 6(c) illustrates how an optimization algorithm used in the embodiment of Figure 6(b) functions;

Figure 6(d) illustrates a system in which wavefront shaping carries out both spatial wavefront shaping and temporal pulse shaping; Figures 7(a), 7(b), 7(c), 7(d) and 7(e) illustrate an optical system according to another embodiment of the present invention; Figures 8(a), ((b) and 8(c) illustrate yet another embodiment of an optical system of the present invention;

Figures 9(a) and 9(b) illustrate yet another embodiment of an optical system of the present invention;

Figure 9(c) shows ta genetic algorithm for optimization used in the embodiment of illustrated in Figures 9(a) and 9(b);

Figure 10(a) illustrates yet another embodiment of an optical system of the present invention;

Figure 10(b) illustrates a pulse having a ring airy beam profile when the pulse outputs the fiber of the embodiment of Figure 10(a);

Figure 10(c) illustrates the use of a phase mask to shape the optical pulse and beam to a desired predetermined wavefront profile;

Figures 11(a) and 11(b) illustrate another embodiment of an optical system of the present invention; Figures 12(a), 12(b) and 12(c) illustrate other embodiments of an optical system of the present invention;

Figure 13 illustrates another embodiment of an optical system of the present invention; and Figure 14 illustrates yet another embodiment of an optical system of the present invention. DETAILED DESCRIPTION OF THE INVENTION

Embodiment 1:

A system according to the present invention is illustrated in Figure 1 and relates to an ablation device or system 11.

Figure 1 illustrates a laser-induced optical breakdown (LIOB) ablation system 11 including an optical source 13 for providing optical pulses, a pulse shaping system 15 configured to modify an optical pulse to compensate for modification imposed on the optical pulse during the passage of the optical pulse to a target site as well as optical waveguide 17 for guiding the optical pulses to the target tissue site. The target tissue site is, for example, a target biological tissue site or area. This site or area can be located inside biological tissue at a given depth or distance from the tissue surface. The optical pulse in such a case propagates through a given depth of biological tissue before reaching the target site or area for ablation. The pulse shaping system 15 is configured to modify a temporal profile or a spatial profile of an optical pulse provided by the optical source 13 to compensate for temporal or spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site. The pulse shaping system 15 provides the modified optical pulse to the optical waveguide 17 for guidance to the subsurface target biological tissue site

The pulse shaping system 15 is configured to modify a temporal profile or a spatial profile of an optical pulse provided by the optical source 13 to compensate for temporal or spatial modifications imposed on the optical pulse while the optical pulse is being guided by the optical waveguide 17.

Alternatively or additionally, the pulse shaping system 15 is configured to modify an optical pulse to compensate for modification of the pulse during passage of the pulse through biological tissue to the subsurface target biological tissue site.

The system 11 includes, for example, a high peak power laser 13 (for example, an amplified Ti: Sapphire laser pumped by a Nd:YAG laser or a fiber laser), an optical pulse or ablation energy shaping system 15 that is wavefront shaping system 15 (or pulse pre-shaping system), and a fiber (or at least one fiber) 17.

The laser 13 delivers a high energy short pulse (for example greater than 0.1 μΐ and shorter than 1000 ps (picoseconds)). The pulse shaping system 15 is configured to modify one or several of the properties of the received pulse such as the pulse duration or the pulse profile in time (pulse temporal profile), or the wavefront spatial profile or a combination of these (for example, the pulse temporal profile and the wavefront spatial profile of the pulse).

The pulse shaping system 15 modifies the spatial phase distribution of the incoming optical pulse. The spatial shape or distribution of the incident wavefront(s) of the pulse is manipulated and modified. The optical pulse with a modified spatial phase distribution (or wavefront) is then provided to the fiber or waveguide input side to be directed or guided towards the target ablation site.

Essentially, the wavefront is the profile of the parts of a beam which are in phase relative to each other. The principle of wavefront shaping by the system 15 to shape or modify the wavefront spatial profile of the light pulse relies on delaying parts of the light beam (for example, using a spatial light modulator, called SLM from hereafter) compared to a reference point of the light beam, thus creating a new propagation profile of the light pulse with different properties. Alternatively or additionally, the pulse shaping system 15 modifies the temporal profile of the incident light pulse. Wavefront shaping is also carried out by modifying the pulse properties in its Fourier plane: in this case, by modifying the frequency components of a pulse by, for example, placing a SLM in its Fourier plane obtained by either a lens or a grating (system 15 including in this case a SLM and a lens or a grating), one can modify the temporal profile of the pulse, for example temporally broadening the pulse, or creating a chirp (relative delay between the frequency components of the pulse).

After such pulse pre-shaping by the pulse modifying system 15, the pulse is then sent through the fiber 17, at the output of which is performed the ablation of the targeted biological tissue.

A catheter in the present case includes at least the fiber 17 but can additionally include the pulse shaping system 15 and/or a mirror to redirect the optical pulse exiting the fiber (as illustrated in Figure 0(b)).

Embodiment 2:

A second embodiment (Embodiment 2) of the present invention includes the same elements as that of embodiment 1 where additionally, at the output of the fiber 17, a focusing system or device 19 is used to focus the pulse of light to a particular target, for example, a targeted site in biological tissue. The focusing system or device 19 includes, for example, a mirror to redirect the optical pulse exiting the fiber 17 to the target site, or a lens, or both. Any optical element permitting to focus the optical pulse can be used instead of the lens. This has the advantage of locally increasing the intensity of light, thus increasing the efficiency and the rate of ablation at the target spot.

Pulse shaping is carried out by the wavefront shaping system 15 to compensate the dispersion the pulse will undergo as it passes through the focusing system 19, in addition to the compensation carried out for the passage through the optical waveguide 17 and/or one or more tissue layers present in an optical path to the subsurface target site. A catheter in the present case includes the fiber 17 and the focusing system 19. Embodiment 3:

Embodiment 3 includes the elements of any one of embodiments 1 or 2 with the following modification. In this embodiment, the wavefront shaping system 15 employs a pulse shaping method involving temporal focusing and the system 15 includes temporal focusing means 21 (Figure 3(a)). The temporal focusing means 21 includes, for example, a SLM and at least one diffraction grating.

The temporal focusing method modulates the duration of the laser pulse to compensate the time dispersion the pulse will undergo as it goes through the fiber 17, and/or the focusing system (for example, a lens) 19, and/or one or more tissue layers between the output of a catheter and the target area (the catheter in the present case includes at least the fiber 17 or alternatively at least the fiber 17 and the focusing system 19).

In fact, the use of a focusing system 19 is optional and we can have temporal wavefront shaping without, for example, a lens 19. Temporal pulse shaping is thus carried out to compensate the temporal dispersion the pulse will undergo as it passes through the fiber 17 and one or more tissue layers to the subsurface target site.

This wavefront shaping is achieved by modifying the pulse properties in its Fourier plane, to influence its temporal profile. The pulse is spatially stretched according to its frequency components by targeting it onto a first diffraction grating. The reflection from the grating allows to influence and manipulate the frequency components of the pulse independently from one another, for example, via a SLM placed after the first grating and using the SLM to selectively operate on some or all of the frequency components. The pulse is then spatially recompressed by the use of a second diffraction grating (which can be the same as the first one or a separate grating) to obtain an output pulse with the same properties as the initial pulse, except for the wavelengths which have been modified using the SLM. Which frequencies are modified, and to what extent these frequencies are modified is obtained by computing/determining an ideal or preferred duration and temporal profile that is to be given to the input pulse in order to obtain a certain or desired output temporal profile at a target site.

One way to do this in the linear optical regime is to send an optical pulse with the desired/expected properties (temporal profile) from the output side of the system (for example, from the target site), where a laser beam with the desired properties is for example transmitted, through a layer of tissue or phantom tissue and then aligned and eventually focused via a lens or objective to enter the fiber via the catheter output or directly at the fiber output, towards the input side (for example, the input side being defined as the input to the optical fiber 17), where the wavefront and/or temporal profile of the pulse are recorded, for example using an optical autocorrelator for the time profile measurement and optionally an holographic setup (Figure 3(d)) for the recording of the wavefront, at said input side, and this pulse is later reproduced as the input pulse to be inputted to the fiber 17 after having been formed by the pulse shaping system 15. The holographic setup includes for example (Figure 3(d)) a laser R producing a reference beam, a hologram recording medium H, an optional mirror 35, the laser 13 producing the pulse whose modified wavefront, after having been passed though the fiber 17 and the other intermediate optical elements, is recorded on the hologram recording medium, the pulse being matched or coupled to the catheter output (in this exemplary case at lens 19) by a microscope objective M (or lens). The hologram recording medium H is preferably a camera and the laser R is used to produce a reference beam which interacts coherently on the camera H with the pulse provided by laser 13 to be measured by the camera H and recorded. For a non-linear regime, other kinds of computation or an empirical characterization of the system for the nonlinear regime can be used. An alternative method to obtain the input pulse characteristics that are to be produced by the pulse shaping system 15 is to pass the pulse through materials which have an optically dispersive profile that is the opposite of that of the fiber 17, and/or lens 19, and/or the upper layers of tissue (upstream of the target site) put one after the other (reversed dispersion means/material) .

Materials have the ability to transmit light at different effective speeds depending on the wavelength of the light. Consequently, a multi-wavelength pulse for which all wavelengths are initially exactly in phase will be temporally broadened after propagating through a certain thickness of a material, since some of its components will have arrived later than others at the output.

To do this, a series of pulses at different wavelengths are propagated (so as to cover the different frequency components of the input pulse that will be used) through the system without pulse shaping, and their delays induced by the system temporal dispersion are measured, for example by using an autocorrelator, (the system including elements such as the fiber 17, and the sample tissue (a sample of tissue with similar optical properties (at least at the used wavelengths) as the tissue through which the pulse will pass and which we want to ablate, or a phantom tissue with these optical properties) in front of (upstream of) a target tissue site) and optionally the focusing system 19.

A pre-shaping system 15 is then created/configured by propagating a starting pulse through different thicknesses of different optical materials whose optical dispersion profiles are known, so as to compensate the above measured whole system temporal dispersion as best possible. In other words, the starting pulse (provided by laser 13) is modified after having passed through the above mentioned pre-shaping system 15 that has been created, and this modified starting pulse is input to optical fiber 17. When this pulse subsequently arrives at the target site, it has undergone temporal distortion that has produced a pulse at the target site having desired or predetermined pulse temporal characteristics for optimal ablation. Use of materials creating such an opposite optical (temporal) dispersive profile has the advantage of shortening the duration of the pulse when it reaches the targeted area, compared to its spread-out duration arising from the passage of the pulse through the fiber, lens and upper layers of tissue. Consequently, it allows the pulse to have a higher intensity of light at the target, thus increasing the efficiency of the ablation as well as the rate of ablation at the target spot, while maintaining a low risk of damaging the ablation device as well as the upper tissue layers.

Figure 3(b) illustrates an example of an experimental set-up for realization of sub-surface ablation at the end of a fiber, using temporal focusing.

A pulse (e.g. 100 fs (femtoseconds) duration, 800 nm central wavelength, 5 μΐ power) is produced by a laser 13. A grating 23 separates its frequency components onto a Spatial Light Modulator 25, where the frequency components are individually delayed to pre-shape the pulse according to the process presented above. The temporal modification of the pulse is predetermined as indicated above and SLM 25 imposes this temporal modification on the pulse provided by the laser 13 and grating 23.

The pulse is then reflected back onto the grating 23 to refocus its frequency components, and, via a beamsplitter 27, goes to a microscope objective 29 which focuses it into the core of a fiber 17. At the output of the fiber 17, a (optional) pair of grated lenses 19 focus the pulse onto the surface of or at a depth inside a sample 33. Mirror 35 is optional. The SLM 25 is controlled via a controller 36 included in a calculator or processor 37 and a control program included in memory 38. The passage of the optical pulse through microscope objective 29 is also taken into consideration during the temporal modification of the optical pulse by the SLM 25 and thus compensated for. In general, any optical element present between the grating 23 and the target ablation area 33 is taken into account during the above described calibration phase and compensated for by the SLM 25. The controller 36 is configured to manipulate the individual pixels of the SLM 25 to temporally modify frequency components of the input optical pulse incident upon the SLM 25.

A catheter can include at least the fiber 17 and optionally the fiber 17 and the grated lenses 19.

Figure 3(c) explains temporal pulse pre-shaping for a simple case of dispersion, where a pulse with only a red and a blue component is considered. The pre-shaping dispersion carried out by system 15 compensates the fiber dispersion. In practice, a higher number of frequency components of the optical pulse are considered as well as dispersion resulting from the passage of the pulse through the biological tissue and any other optical elements that are used to carry out ablation, but the principle of compensating their temporal shift stays the same. For the pulses represented in Figure 3(c), the vertical axis represents the measured power, and the horizontal axis represents measurement time. Embodiment 4:

Embodiment 4 of the present invention includes the elements of any one of embodiments 1, 2 or 3 wherein the fiber 17 which is used is a single-mode photonic crystal fiber (Figure 4(a)). The single-mode photonic crystal fiber 17 has a core filled with air or another gas, making it less prone to internal damage at very high peak pulse power compared to normal single mode silicon fiber. Since we use very high peak power pulses, there is a risk of creating an internal plasma inside a fiber and damaging the fiber. This risk is reduced in this embodiment of the present invention.

Current single-mode photonic crystal fibers, for example, have a core diameter of approximately 20 μπι or less and an overall diameter of approximately 500μιη or less (considering core, cladding, and a protective layer) which makes it very small compared to the main arteries of the human body, and thus very appropriate for integration into a catheter. Embodiment 5:

Embodiment 5 of the present invention includes the elements of any one of embodiments 1, 2 or 3 and wherein a multimode fiber is used, for example, a multi-mode large mode area (LMA) fiber is used (Figure 5(a)) or a fiber bundle.

This fiber advantageously has a very large silicon core where the optical intensity spreads out over a large area (several hundreds of squared micrometers), making it less prone to internal damage at very high peak pulse power compared to normal silicon fiber.

Since very high peak power pulses are used, there is a risk of creating an internal plasma inside a fiber 17 and damaging the fiber. This multimode fiber significantly reduces this risk. The multimode fiber has, for example, a core diameter larger than 50 microns and an overall diameter up to a few millimeters (considering core, cladding, and a protective layer) which make it usable in a catheter for the main arteries of the human body.

Embodiment 6:

Embodiment 6 includes the elements of embodiment 5 with the following modification. In this embodiment, the wavefront shaping (pre-shaping) system 15 used comprises spatial wavefront shaping (Figure 6(a)) which is carried out without the temporal pulse shaping described previously in embodiment 3, or can be complementary to the temporal pulse shaping and used in addition to temporal pulse shaping (for example, illustrated in Figure 6(d)). This wavefront shaping is performed using for example a spatial light modulator (SLM) or a digital micromirror device (DMD) for modulating the different modes of the light going through the multimode fiber, independently of one another.

In this embodiment, a SLM is, for example, placed to reflect the pulse coming from the laser 13 to the input of the fiber 17, and set so that each of its pixels (or groups of pixels) are addressed and able to tune and modify the inputs on the SLM to modify the wavefront of the optical pulse to transfer energy to particular modes of the optical fiber 17, entirely or partially independently from each other. A particular input (one or more pixels or a group of pixels) on the SLM reflecting energy to the fiber 17 can thus increase the amount of light going through one or several modes of the fiber 17, at the expense of some other modes. Figure 6(b) shows in more detail an optical system which is be used for this purpose. Figure 6(b) illustrates a pulse (e.g. 100 fs (femtoseconds) duration, 800 nm central wavelength, 5 μ3 power) produced by a laser 13. A Spatial Light Modulator 39 (SLM) shapes the pulse as described above. The pulse is then reflected back via a beamsplitter 41, goes to a microscope objective 43 which focuses it into the core of a fiber 17. At the output of the fiber 17, a pair of (optional) grated lenses 19 focus the pulse onto the surface of or inside a sample 45. Mirror 35 is optional.

As previously mentioned, a catheter can include at least the fiber 17 and optionally the fiber 17 and the grated lenses 19. This spatial wavefront shaping compensates for various types of disturbances that the pulse will undergo as it propagates through the fiber 17 (for example, due to bending or imperfections of the fiber 17) and/or in the upper layers of the tissue 45 (due to scattering) in which ablation is carried out (and the lens 19 when used). This embodiment includes a calculator or processor 47 for generating a random wavefront to be applied to or imprinted on the optical pulse by the SLM 39 and a memory 49 storing an algorithm for generating a random wavefront that is executed by said calculator 47 to generate the random wavefront (Figure 6(b)). The system further includes a controller 50 configured to receive the generated wavefront and configured to manipulate the individual pixels of the SLM 39 to apply the generated wavefront to the input optical pulse incident upon the SLM 39. Pulse modification data is generated by the calculator 47 and provided to the controller 50 to manipulate the individual pixels of the SLM 39 and to modify the wavefront of the optical pulse provided by the laser 13.

The system additionally comprises means 51 for measuring a value representing the generated light intensity, such as, an optical power meter or optical detector for measuring the light intensity generated at the target spot or a device 103, 107, 109 to measure a generated acoustic signal generated by the optical ablation pulse (such as the device described later in embodiment 13, Figure 13(a)). The means 51 are also configured to communicate a value representing the generated light or acoustic wave intensity to the calculator 47 (for example, via a data transmitter/receiver of the calculator 47 and a data transmitter/receiver of the optical power meter or optical detector interconnected through a cable or wirelessly). The calculator 47 is configured to repeat the above process multiple times in order to obtain a maximized light intensity/optical power (or acoustic signal) at the targeted spot.

The calculator 47 is connected and in communication with the SLM 39 to drive the pixels of the SLM 39. The algorithm randomly generates a wavefront to phase shift the spatial components of the pulse wavefront as the algorithm controls the phase shift induced by individual pixels or groups of pixels of the SLM 39, while also receiving a measurement of the light emitted by a plasma generated at the targeted spot (in the tissue) in order to optimize and maximize the light intensity measured at the targeted spot. The light emitted by the plasma is measured using for example optical detector 51 connected and in communication with the calculator 47. Alternatively, the optical detector 51 can be replaced by an acoustic detector. The optical detector 51 or the acoustic detector can, for example, be located in the catheter at one of its extremities in addition to the fiber 17 (and optionally the focusing system 19). The article entitled "Genetic algorithm optimization for focusing through turbid media in noisy environments" by Conkey et al, Optics Express, 2012 provides details of how random wavefronts are generated. This process is repeated multiple times to increase the quality of optimization. The generated wavefront for which the light intensity signal from the generated plasma measured by the optical detector 51 (or another optimization signal such as an acoustic signal from the ablation side or an optical signal modified by the light intensity at target area) is the strongest is then maintained and ablation is carried out using this optimized wavefront and SLM configuration.

In general, optimization can be carried out in-vivo. For example, the optimization can be carried out using a lower power laser pulse and, once optimization is achieved, a laser pulse of increased power is used for ablation. Alternatively, a high power pulse is optimized from the start permitting ablation at deeper and deeper depths into the tissue as optimization advances. Alternatively, the ablation pulse can already be compensated to some extent (for example, by being temporally pre-shaped already when optimization of the wavefront profile begins, or being only spatially compensated for the passage through fiber 17 via a recorded hologram when optimization of the wavefront profile begins (as detailed in Embodiment 7)) when optimization is started and optimization then begins from this starting basis to (quickly) provide a pulse that is optimally compensated and producing a desired ablation.

Figure 6(c) presents the way the optimization algorithm functions. A first step includes the generation of a random wavefront by the calculator 47 for spatially re-shaping the laser pulse wavefront. The calculated wavefront is then inputted to the SLM 39 to reconfigure the pixels of the SLM and the re-shaped pulse is reflected from the SLM 39 to the target site through the fiber 17. Monitoring of an impact of the pulse at the target site is carried out via the signals provided by the optical (or acoustic) detector 51. An evaluation is carried out of the detected signal by comparing the detected signal to previously measured signals, for example based on the measured light intensity. Further different wavefronts are generated as indicated above until the evaluation determines the pulse spatial wavefront and SLM 39 configuration permitting optimum ablation (for example, that where the generated light intensity is maximum).

Figure 6(d) illustrates an example of a system in which the wavefront shaping (pre-shaping) system used carries out both spatial wavefront shaping and temporal pulse shaping. In Figure 6(d) a pulse provided by the laser 13 is temporally modulated in a first arm Al including beamsplitter 27, grating 23 and, for example, a first SLM 23 before being spatially modulated in a second arm A2 (beamsplitter 27 providing the temporally modified pulse to the second arm A2) including beamsplitter 41 and second SLM 39. In this case, a beamsplitter 27, a grating 23 and SLM25 are used before the spatial modulation set-up, in a way identical to what has been presented in Figure 3(b). The calculator 47 is also in communication with the first SLM 25 and configured to drive the pixels of this first SLM 25 as previously described in relation to Figure 3(b) and embodiment 3. Embodiment 7

Embodiment 7 includes the elements of embodiment 6 with the following modification. In this embodiment, the wavefront shaping (pre-shaping) system 15 does not use a random algorithm as done in the previous embodiment (an algorithm to generate a SLM configuration to modify the wavefront spatial profile of the incident optical pulse to produce a modified wavefront for optimized ablation), but the wavefront spatial profile modification described in the present embodiment instead relies on a deterministic holographic method to shape the pulse at the output of the fiber 17. For this purpose, as illustrated in Figure 7(b), a hologram is first recorded at the light pulse input side of the fiber 17 when a particular desired E-field is present at the output side of the fiber 17 (produced by laser 13 and pulse shaping system 55 in Figure 7(a)), this field being the field one expects to have on the output side during the ablation process (Figure 7(a)). The system of Figure 7(b) is identical to that of Figure 3(d) described above in Embodiment 3.

For this recording of a hologram, a holographic recording medium 57 is used, for example light-sensitive photoresist or photopolymer or a medium for recording a digital hologram. Once the hologram 59 is recorded, it is used to shape a beam and pulse that is then inputted to the fiber 17, to produce a wavefront having the desired/expected field at the output of the fiber 17 or at the target tissue site 53 (Figure 7(c) and (d)). This can effectively be used to correct the dispersion and other aberrations (e.g. bending losses) coming from a fiber 17, when the fiber 17 is of a particular configuration (predetermined length, bending radius and location, etc).

As illustrated in Figure 7(d), this embodiment compared to the previous embodiment 6 does not include a calculator 47 for generating a random wavefront, a controller 50 configured to receive the generated wavefront or means 51 for measuring a value representing the light intensity generated at the target spot. The SLM 39 and the beamsplitter 41 are for example replaced by the recorded hologram 59. The focusing lens 43 is optional.

A catheter in the present case includes the fiber 17 and optionally the recorded hologram 59 and/or the focusing system 19. Furthermore, the present invention concerns a deterministic characterization of the fiber 17 to shape the pulse at the output of the fiber 17 using a stored library of values created using holography recordings, and produces new wavefronts from this library. This permits a desired spatial distribution or wavefront profile of the light pulse to be generated at the output of the fiber 17.

A holographic recording medium 57 is used to record the holograms, for example light- sensitive photoresist or photopolymer or a medium for recording a digital hologram as described above (see also Figure 7(b)). A library of wavefront profiles at the input of the fiber and of the corresponding pulse profiles after transmission through of fiber 17 is determined. To do so, a plurality of holographic recordings of an E- field spatial distribution (wavefront profile) at the input side of the fiber 17 is carried out for different desired E-field spatial distributions at the output of the fiber 17 (as described previously and illustrated in Figure 7(b)). For example, a first hologram recording is created in order to modify the wavefront profile of the pulse provided by the laser 13 to generate a focused laser spot at first predetermined spatial location at the output of the fiber 17. A second hologram recording is created in order to modify the wavefront profile of the pulse provided by the laser 13 to generate a focused laser spot at second predetermined and different spatial location at the output of the fiber 17.

This for example permits a laser focused spot to be produced at a desired spatial location at the output of the fiber 17. This also permits a plurality or an array of laser focused spots to be produced at the output of the fiber 17 from the same pulse provided by the laser 13. The plurality of focused laser spots can be in the same focus plane or could each be focused at different depths.

A library of holographic recordings of E-field inputs and the corresponding E- field outputs is thus established. By linearly combining parts of different input E-fields from this library, we can shape the output E- field profile in order to produce a desired E-field spatial profile at the output of the fiber 17 at a particular desired location.

An example of the use of this method to create a single light spot at the output of the fiber 17 (at a specific location after (or upstream of) the output end of the fiber 17) is as follows. A beam of light is focused, with the desired properties or similar properties as that of the (focused) ablation light, at the output of the fiber 17 by, for example, varying the spatial distribution of the E-field at the input side of the fiber 17. The E-field on the input side of the fiber 17 producing this desired focused ablation beam is then simultaneously recorded, for example with a camera, a reference beam, and the computing of the incident wavefront using the holography method presented above. To record the hologram on the camera, the beam being studied and the reference beam are both targeted on the same location of the camera. The pattern recorded on the camera is the hologram. To recreate the beam which was studied during the hologram recording, one has to replace the camera by an SLM and, as an example of a simple reconstruction method, input pixel values in the SLM replicate the interference pattern recorded, in a way that the areas of maximum constructive interference are given the values for no phase delay, and the areas of maximum destructive interference are given values for maximum phase delay. The recordings are stored in the library. The input parameters sent to the SLM for reconstruction have been prerecorded, and it is this information and recordings which are used to recreate the expected wavefront at the output.

We then replace the camera with an SLM 739 as illustrated in Figure 7(e), and use it to shape the wavefront of a new input pulse to obtain the E-field recorded with the camera, and send it to the input side of the fiber 17 to be inputted into the fiber 17.

The system includes a calculator 747, a controller 750 and memory 749. The calculator 747 provides the selected digital hologram from the library stored in memory 749 to the controller 750. The controller 750 is configured to manipulate the individual pixels of the SLM 749 to apply the digital hologram to the input optical pulse incident upon the SLM 739. Pulse modification data is generated by the calculator 747 and provided to the controller 750 to manipulate the individual pixels of the SLM 739 and to modify the wavefront of the optical pulse provided by the laser 13.

Doing so, at the output of the fiber 17, we recover the single light spot (the desired light spot for ablation) or other specific pulse profile we initially had (but propagating away from the output).

To populate the library, the whole process of recording for different single spots on the output side of the fiber or catheter is repeated, and a corresponding library of recordings is built-up. This library is used to store the spatial wavefronts of each spot and the corresponding values are used as inputs to the SLM to configure the pixels of the SLM. One can obtain at the output side of the fiber 17, a set of illuminated single spots of which the corresponding input wavefront was added on the SLM. That is, addressing signals based on the library values are applied to the SLM to produce a spatial wavefront profile on an input pulse that subsequently propagates through the fiber 17 and produces the desired ablation spot upstream from the output of the fiber 17.

In the case where a library of holographic recordings are created using for example a non- digital medium 57 such a light-sensitive photoresist or a photopolymer, one or more of these recordings are positioned individually or in series at the hologram recording 59 location illustrated in Figure 7(d) in order to produce a single focused spot or a plurality of spots at the output of the fiber 17.

Embodiment 8

Alternatively, embodiment 7 can also be employed in a complementary manner in combination with the method and system of previous embodiment 6 (as indicated by pulse-pre-shaping system 63 in Figure 8(a) and illustrated in Figure 8(b)) and also use a random algorithm as done in the previous embodiment 6 (an algorithm randomly generating a SLM configuration to phase shift the spatial components of the pulse wavefront to produce a specific wavefront) and in such a case this embodiment 8, like embodiment 6, includes the calculator 47 for generating a random wavefront, the controller 50 configured to receive the generated wavefront and means 51 for measuring a value representing the light intensity generated at the target spot 45. As illustrated in Figure 8(a) and Figure 8(b), the hologram 59 modifies the spatial profile of the pulse provided by the laser 13 and this hologram modified pulse of modified wavefront is provided as a basis pulse to the SLM 39 to be further modified by the optimization algorithm. The random algorithm generates a wavefront profile that modifies the optical pulse wavefront produced by the hologram 59 via the SLM 39 configuration corresponding to the generated wavefront to phase shift the spatial components of the pulse wavefront produced by the hologram 59. The optimization process as described in Embodiment 6 is then carried out to obtain an optimized ablation pulse at the target site.

The hologram 59 provides a pulse to the SLM 39 that is compensated for the perturbation (due to dispersion for example) the pulse will occur during its passage through the fiber 17. The optimization process is thus carried out on this compensated pulse via SLM 39 to further compensate for the passage of the pulse through the biological tissue to the target ablation site. As before, this optimization is carried out until a pulse is shaped by the SLM 39 that provides desired ablation properties at the target ablation site. The hologram 59 is taken from the library of holographic recordings and, for example, a non-digital medium 57 such a light-sensitive photoresist or a photopolymer is used in Figure 8(b).

Figure 8(c) illustrates the case where the hologram 59 is a digital hologram taken from the library of holographic recordings. The same SLM 739 is used to apply the digital hologram to the input optical pulse incident upon the SLM 739 and to modify the wavefront profile of said pulse in accordance with the profile generated by the random algorithm.

The calculator 47 provides a (selected) digital hologram from the library stored in memory 49 to the controller 50. The controller 50 is configured to manipulate the individual pixels of the SLM 739 -to apply the digital hologram to the input optical pulse incident upon the SLM 739 (as described previously in relation to Figure 7(e)). Pulse modification data is generated by the calculator 47 and provided to the controller 50 to manipulate the individual pixels of the SLM 739 and to modify the wavefront of the optical pulse provided by the laser 13. This is the basis pulse (hologram modified pulse) that has compensated for the perturbation the pulse will occur during its passage through the fiber 17 and whose wavefront profile is then modified by the optimization process implemented by the calculator 47 (described in relation to Embodiment 6) to further compensate for the passage of the pulse through the biological tissue to the target ablation site.

Thus, in this embodiment 8, one is recording, and possibly optimizing, the different input wavefronts corresponding to different beam profiles at the output of the catheter, thus constituting a library. The user can then input a specific wavefront from this library by placing the correct holographic medium 59, 739 between the laser 13 and the fiber 17 to obtain one of the registered output profiles at the fiber output. T One can for example record the profiles corresponding to separate focus spots and use the corresponding library to choose how he would later want to focus the beam. The optimization algorithm can be run on one of the wavefront profiles taken from such a library of wavefront profiles. Embodiment 9: Embodiment 9 includes the elements of embodiment 6 with the following modification. In this embodiment, the wavefront shaping system 15 is the same as in embodiment 6, but the algorithm to optimize the generated wavefront used to shift the spatial components of the incident pulse on the SLM (for example) is specifically a stochastic genetic algorithm (Figure 9(a)). The article entitled "Genetic algorithm optimization for focusing through turbid media in noisy environments" by Conkey et al, Optics Express, 2012 provides details of how this algorithm is used for optimization.

According to this algorithm, an optimization value for a set of input parameters is measured, the best of these sets of parameters is selected, and elements of the selected set are then mixed with each other to obtain new sets of parameters. The mixing is made with random mutations and cross-overs between the best evaluated wavefronts.

Figure 9(b) presents the use of a genetic algorithm for intensity optimization. In the case of a wavefront shaping using an SLM, the parameters randomly generated are the phase-shift values applied by the different pixels, or sets of pixels of the SLM to an incident optical pulse. The optimization is carried out in order to obtain a desired focused light pulse at a target ablation site that generates, for example, a maximum light intensity value.

We then use these new sets of parameters (the phase-shift values applied by the different pixels) and measure the corresponding optimization value (maximum light intensity value at ablation site), and repeat the previous steps several times until we obtain a desired predetermined optimization value.

As illustrated in Figure 9(b), the present embodiment also includes a calculator 965 for generating a population of random candidate wavefronts (based on the algorithm stored in memory 966), a controller 967 configured to receive the candidate wavefronts and configured to manipulate the individual pixels of the SLM 969 to apply the wavefronts to the input optical pulse incident upon the SLM 969, and a system 971 for measuring an optimization value dependent on the quality of focus, that is, for measuring a value representing the focused light intensity at the target site 973 such as an optical power meter, optical camera or detector, or an acoustic signal measurement device (13103, 13107, 13109 of embodiment 13)), and configured to communicate a value representing the light intensity at focus or the focus quality to the calculator 967. The calculator 967 is configured to rank and select wavefronts, based on said value and to mutate and mix the best wavefronts generated by the algorithm and producing high or near maximum light intensity value at the ablation spot. The calculator 967 can run this cycle of ranking, selecting and mixing on several successive generations of wavefronts in order to obtain a maximized light intensity at the targeted spot, or reach a predetermined quality of focus. As illustrated in Figure 9(c), a first step includes the generation of a population of random wavefronts by the calculator 965, each wavefront being for spatially re-shaping the laser pulse wavefront when used as inputs to the SLM. An algorithm generated wavefront is then inputted to the SLM 969 to reconfigure the pixels of the SLM to modify the wavefront of the optical pulse provided by the optical source to reproduce the algorithm generated wavefront. The re- shaped pulse is reflected from the SLM 969 to the target site 973 through the fiber 17. Monitoring of an impact of the pulse at the target site is carried out via measurement signals provided by the optical (or acoustic) detector 971. This is repeated for each generated wavefront of the population. An evaluation is carried out of the measured detected signals to rank and select the best wavefronts. The best wavefronts are mutated and mixed and the above process repeated using these mixed and mutated wavefronts in order to obtain a maximized light intensity at the targeted spot/site, or reach a predetermmed quality of focus.

The stochastic genetic algorithm and optimization method of this embodiment can alternatively be used instead of the random algorithm in Embodiment 8. Embodiment 10:

Embodiment 10 of the present invention includes the elements of any one of embodiments 6, 7, 8, 9 or 12 (as later described) with the following modification. In this embodiment, the wavefront shaping (pre-shaping) system 15 is used for the purpose of generating an optical pulse having a beam profile with auto-focusing properties, and is compatible with the wavefront optimization process, of changing the beam profile at the output of the fiber (Figure 10(a)). In this embodiment, the method of one of the above mentioned embodiments is used to determine/compute the optical E-field (E-field spatial distribution) which is needed at the input of the fiber 17 to obtain a particular optical E-field (E-field spatial distribution) at the output of the fiber 17. In this embodiment of the present invention, a pulse pre-shaping method of any one of embodiments 6, 7, 8, 9 or 12 is used so that the quality of ablation of the target area is enhanced while simultaneously limiting as much as possible or eliminating damage to the surrounding tissues, in particular the tissue present between the surface of the sample tissue and the target site.

The wavefront shaping (pulse pre-shaping) system 15 is configured to generate an autofocusing pulse that focuses to a predetermined target ablation site, without the interaction or presence of any optical focusing element, when the pulse exits the fiber 17. Examples of such beams are ring Airy beams, Bessel beams, Pearcey beams and accelerating parabolic beams.

The pulse shaping system 15 is thus configured to generate an optical pulse having a beam profile with auto-focusing properties.

The wavefront shaping (pulse pre-shaping) system 15 is configured to generate a beam that is unfocussed (defocused) at the surface of the sample tissue, and in-focus at the target site (see for example Figure 0(c)). The presence of a focusing system 19 or a lens 19 or other optical element between the fiber and the target site is optional and if present, it is taken into consideration by the wavefront shaping (pulse pre-shaping) system 15 so as to still generate a beam that is unfocussed (defocused) at the surface of the sample tissue, and in-focus at the target site. For example, a mirror or reflecting element may be used to redirect the pulse exiting the fiber 17 to a target ablation site. The pulse is thus shaped to make the beam unfocused at the surface of the sample tissue, and make it in-focus at the target area, with or without the use of a focusing system or a lens 19. The wavefront shaping (pulse pre-shaping) system 15 is configured to generate a self-focusing beam having:

(i) an energy repartition that is spatially spread-out at the surface of the sample (or energy entry point into a tissue sample) to minimize or eliminate tissue damage at that energy entry point, and

(ii) an energy repartition that is spatially concentrated specifically at the subsurface target location to confine tissue damage to that particular and desired location. For example, the pulse shaping system 15 is configured to produce a pulse having a ring airy beam profile (Figure 10(b)) when the pulse outputs the fiber 17.

Advantageously, this beam profile focuses by itself to a target area as it propagates forward. In this way, a focusing system or lens 19 is unnecessary, and at the same time, due to the energy repartition in the generated ring airy beam, a better ratio between the power at the surface of the sample and at the subsurface target location, compared to typical Gaussian beams used in the prior art is advantageously achieved.

In other words, using this technique of the present invention to shape the beam profile allows to further decrease or minimize the risk of damaging the tissue surface during the operation, and additionally allows to reach deeper subsurface targets for ablation.

Figure 10(b) shows in 10(b)(1), 10(b)(3), and 10(b)(5), a transversal or cross-sectional intensity profile of the ring airy beam after output from the fiber 17, and 10(b)(2), 10(b)(4), and 10(b)(6) show a longitudinal intensity profile (or intensity profile in the propagation direction of the pulse) of the ring airy beam as it propagates in free space (over a distance of 240μηι, 170μπι, and 60μηι, respectively). As can be seen from Figure 10(b), the intensity along the propagation axis rises strongly after a certain (desired and predetermined) distance (see arrow on 10(b)(2), 10(b)(4), 10(b)(6)), efficiently focusing the beam without the use of a lens 19 or other optical focusing element.

The ring airy beam profile is only one example of a pulse/beam profile that can produce the above results using the above described technique. Other auto-focusing pulses can be generated using other profiles such as a Bessel beam profile, a Pearcey beam profile or an accelerating parabolic beam profile.

This embodiment of the invention thus first relates to a method and system for producing a particular light beam profile having a desired spatial energy distribution (for example see Figure 10(b)), and secondly to the generation of an auto-focusing optical pulse once the pulse exits the fiber 17. Each one can be performed independently to achieve the objective of the present invention or preferably both are performed.

To proceed with the beam shaping of the present embodiment, a multimode fiber 17 is preferably used (for example, the multimode fiber as presented in previous embodiment 5 or 6) to do such spatial beam shaping, or alternatively a pulse shaping system located after the exit of a single-mode fiber can be used, as will be shortly presented in embodiment 12.

Any one of the systems presented in embodiments 6, 7, 8, 9 (or 12) can be used to obtain the desired wavefront at the output of the fiber 17, by using more specifically the methods presented in embodiments 6, 7, 8 or 9 with the following modifications. That is, the random algorithm approach of Embodiment 6 is used to determine a spatial distribution of the optical pulse wavefront to be inputted to the fiber 17 that produces a pulse having, for example, a ring airy beam profile when the pulse outputs the fiber 17 and that auto- focuses, once or after the pulse exits the fiber 17, to a predetermined target ablation site.

The random algorithm approach is used to determine a spatial distribution of the optical pulse wavefront to be inputted to the fiber 17 that produces, at the output of the fiber 17, an E-field spatial distribution at a predetermined distance from a target ablation site corresponding to the surface of the target sample (or energy entry point into a tissue sample) that minimizes or eliminates tissue damage at that energy entry point, while focusing at a subsurface target location of said tissue to confine tissue damage to that particular and desired target location. Optimization is carried out on the E-field spatial distribution of the optical pulse at one or more locations along the propagation direction after the fiber 17 or catheter output but before the target ablation site.

An optimization can be carried out by measuring the optical intensity spatial distribution at a predetermined location after the output of the fiber or catheter (using a camera for ex-vivo for example, or an OCT monitoring the light intensity or the ablation-dependent cavitation for in- vivo example) and computing a correlation value (for computing such a correlation value see, for example, "Adaptive shaping of complex pulsed nondiffracting light fields" by M.Bock et al., 2011 Complex Light and Optical Forces) for this measured distribution with a desired E- field spatial distribution. This correlation value increases when the measured E-field value(s) at the output of the fiber/catheter becomes more similar to the desired E-field distribution.

The desired E-field spatial distribution at a given location along the propagation direction, to which the measured intensity distribution is correlated to, is determined by the beam profile used to produce an optical pulse with auto-focusing properties. Optimization is carried out to obtain the generated wavefront that produces the highest correlation value. This can be done for at least one predetermined location after the output of the fiber or catheter or a plurality of predetermined locations.

Alternatively, a combination of a hologram recording of Embodiment 7 and the random algorithm approach of Embodiment 6 can be used as set out above in Embodiment 8.

Likewise, the genetic algorithm of embodiment 9 can alternatively be used to obtain and determine the spatial distribution of the optical pulse wavefront to be inputted to the fiber 17 to produce a pulse at the output of the fiber 17 with the above mentioned properties.

To use the method employing a stochastic genetic algorithm presented in embodiment 9, rather than running an optimization on the value representing the light intensity generated close to or at the ablation target site, we run an optimization on a parameter which gives an indication of how much the E-field spatial distribution at the output of the catheter or fiber 17 is similar to the E-field spatial distribution we want to obtain at this particular location or area in the propagation direction of the optical pulse. One measurement of the whole E-field at the output of the fiber 17 (for example with a camera directly at the output of the fiber) is necessary to verify that a Bessel Beam profile for example is being generated or produced. Nevertheless, in addition, this E-field spatial distribution measurement (or E-field spatial distribution measurement in a plane substantially perpendicular to the direction of propagation of the pulse) can be done separately for a plurality of different locations along the propagation direction after the fiber or catheter output, by displacing a measurement device (for example a camera) to these measurement locations. An example of how such an optimization value can be obtained is by measuring the optical intensity of the E-field at the output of the catheter (using a camera for example) and computing its correlation value (as mentioned previously) with a desired E-field spatial distribution. This correlation value increases when the measured E-field value(s) at the output of the catheter becomes more similar to the desired E-field distribution, as the optimization algorithm selects and mixes input wavefronts. A measurement of the E-field spatial distribution at a location along the propagation direction of the pulse can be carried out in- vivo using the acoustic signal measurement device described in Embodiment 13 (a transducer, an electrical cable, and an amplifier and processor) measuring an acoustic signal coming from an ablation site or using an Optical Coherence Tomography (OCT) system. A shift of the location of measurement is carried out to measure the E-field spatial distribution at different locations.

The desired E-field spatial distribution at a given location along the propagation direction, to which the measured intensity distribution is correlated to, is determined by the beam profile used to produce an optical pulse with auto-focusing properties.

Optimization is carried out to obtain the generated wavefront that produces the highest correlation value. This can be done for at least one predetermined location after the output of the fiber or catheter or a plurality of predetermined locations. Alternatively, we can use one of these techniques to design a phase mask 1003 to be put at either end of the fiber, and which shapes the beam to the correct profile (see Figure 10(c)).

In essence, rather than actively modifying the wavefront by one of the mentioned embodiments, using an electronic system (SLM), we replace or complete it by optical elements 1003 with set properties that permit a self-focusing beam with the above mentioned characteristics to be produced.

In practice, we would use one of the wavefront optimization methods described above and in one of the previous embodiments of this invention to find the properties of an appropriate pulse wavefront (pulse wavefront spatial profile) to be provided at the input of the fiber and that produces a desired self-focusing pulse at the output of the fiber 17.

Common clean room facilities fabrication processes are used to fabricate a specifically-tuned phase mask optical element 1003 mimicking the wavefront-shaping properties of an SLM in the configuration which would produce the desired input wavefront to the fiber 17 (see for example "Field Guide to Optical Lithography" by C.A.Mack (Print ISBN13: 9780819462077)). Essentially, the phase mask 1003, for example working in reflection like an SLM, is then a reflective surface with deeper areas (thus inducing delay compared to the light reflected by the higher areas) to mimic the time delay created by the SLM when it is in the configuration creating the wavefront to be replicated.

For example, an optical element 1003 such as an axicon (which transforms a collimated Gaussian beam into a Bessel Beam) shapes the beam to give it a Bessel beam profile, and is added at the output of the single-mode fiber (see embodiment 12), rather than using an SLM for the same purpose. However, dynamic wavefront shaping techniques are then still compatible with the simultaneous use of such an optical element, and can still be useful for time-shaping (as for example carried out with the system of embodiment 12) and corrections of the wavefront. Embodiment 11:

Embodiment 11 includes the elements of any one of embodiment 6, 7, 8, 9 or 12 (see later) with the following modification. The wavefront shaping system 15 is the same as in embodiment 6, 7, 8, 9 or 12 with the difference that at least one device 1199 configured to simultaneously monitor and measure two different optimization values for feedback to an algorithm is included. That is, at least one device measures and provides a value, to the calculator 47 for example (Figure 11(b)), representing the light intensity at a first particular location (representative of the focusing/defocussing quality at a particular location) and a second particular location, and a single algorithm receives these two values and optimizes the generated wavefront based on the values provided by the device 1199 (Figure 11(a)).

The first optimization value is acquired through monitoring of the beam intensity substantially at the sample or tissue surface, where limited, minimized or preferably no damage is desired, while the second optimization value is acquired through monitoring of the beam intensity at the subsurface target tissue area, where we want to maximize the intensity. For example, the first measured optimization parameter at the tissue surface is the intensity of the light coming from the sample surface, detected by a photodiode on or in the catheter (or a photodiode to which the fiber 15 collects and guides light back from the output end to the input end) or alternatively an optical power meter or optical detector, and the second measured optimization parameter (value) representing the intensity at the subsurface target tissue area is an opto-acoustic signal measured for example using the acoustic-setup 13103, 13107, 13109 as later detailed in embodiment 13. In the system of this embodiment, the optimization value corresponding to the intensity at the sample surface (optimization value 1) must be lower than a predetermined particular value representing the threshold inducing damage to the tissue surface. At the same time, the optimization value corresponding to the intensity at the subsurface target area (optimization value 2) must at least reach a certain predetermined value for ablation to happen, and it must be optimized to reach at least this particular value.

For example, the optimization process is as follows. A series of optimization runs is carried out to increase (improve) the optimization value 2 (subsurface), following the procedure for example presented in embodiment 9 allowing one to start with a good/desired quality focus in depth.

To limit the damage at the surface of the tissue/sample, the output from the above previous simulations on optimization value 2 (subsurface) are used as input to run a cycle of optimization on optimization value 1 (surface), following the procedure presented in embodiment 9 for example; that is first generate a random set of wavefronts to be displayed on an SLM at the input side of the fiber, evaluate their independent impacts on the measurements of the optimization value 2, select the best ones, randomly mix them with each other, we use the new wavefronts obtained that way as the new set of input wavefronts; one can repeat these steps several times to increase as high as desired the optimization value 2. We repeat the process using the output of the previous simulation as input for the following one, alternating between the two optimization values 1 and 2. After a certain number of runs we obtain a compromise on the optimization of the two optimization values, ideally reaching a set value for both of them. In a case where a compromise has to be found, a bias toward one of the target values can be induced in the optimization algorithm, for example by running more iterations to optimize one optimization value than for the other.

The number of optimization values can be increased to as many as we have observable values to monitor. For example, from the example given in the previous paragraph, we can add a third optimization value that is measured and corresponds to a maximum intensity reflected by an interface of a catheter at the output of the fiber 17. The corresponding value could be monitored by a photodiode measuring the light at the laser wavelength that is reflected from the output interface of the catheter toward the input of the fiber 17. In this example, a compromise between the three optimization values has to be found.

Embodiment 12: SLM at output of hollow-core fiber

Embodiment 12 includes the elements of embodiments 4 with the following modification. In this embodiment, a wavefront shaping device 12101 (e.g. including a SLM) is included and placed at the output of the hollow-core fiber 17 (Figure 12(a)).

Having a wavefront shaping device 12101 at the output of the fiber 17 allows to additionally do spatial wavefront shaping at the output of the fiber 17, in a way which is complementary to the temporal wavefront shaping carried out by pulse pre-shaping system 15 and previously described in embodiment 3.

Figure 12(b) illustrates such a system including the elements of embodiment 3 and additionally including element to carryout wavefront spatial profile shaping of the pulse outputted from fiber 17. For example, the system includes an SLM 12103, beamsplitter 12105 and lens 12107. These elements are used to carry out the carryout wavefront spatial profile shaping previously described in any one of Embodiment 6, 7, 8, 9, 10 or 11.

Consequently, this embodiment uses, (applied to the pulse exiting the single mode fiber) the wavefront shaping methods presented for multi-mode fibers in embodiments 6, 7, 8 and 9 as well as 10 and 11, where the wavefront shaping device 12101 optimizes the signal intensity/power at the target for a pulse passing from the output of the hollow core fiber to the target area. Instead, or in addition to, an SLM 12103, another means for wavefront shaping of the optical pulse at the output of the fiber 17 is a phase mask 12109 (see Figure 12(c)) to give the beam the desired profile at the focus or other areas in the direction of propagation. For example, an axicon 12109 at the end of the fiber (which transforms a collimated Gaussian beam into a Bessel beam) shapes the beam from the fiber 17 to give it a Bessel beam profile and produces a Bessel beam, which beam can further be optimized by wavefront shaping elements or SLM 12103, as illustrated in Figure 12(c). As mentioned above, axicon 12109 can alternatively be used solely at the output of the fiber to produce an autofocussing pulse with the advantageous properties of such a pulse mentioned previously in Embodiment 10. A catheter according to the present invention includes the fiber 17 and the pulse shaping device 12109. Preferably, the pulse shaping device 12109 is located after the output end of the fiber 17 in a head of the catheter. The catheter can also include other elements such as a lens, for example, located after or upstream of the pulse shaping device 12109. A catheter according to the present invention may also include the fiber 17 and the pulse shaping device 59 or 1003 as described in embodiments 7 and 10. Preferably, the pulse shaping device is located at the input end of the fiber 17. Embodiment 13: Acoustic signal as beacon

Embodiment 13 includes the elements of any one of embodiments 6, 7, 8, 9, 10 or 12 with the following modification. In this embodiment, we use an acoustic signal from the ablation process, or the opto-acoustic response of the tissue, as the optimization value for the optimization algorithm (Figure 13(a)).

In this embodiment, an acoustic set-up is used in parallel to our optical set-up. The acoustic setup is used for monitoring the ablation, and comprises a transducer 13103 close to the ablation site 13105, an electrical cable 13107 collinear to the optical fiber 17, and an amplifier and processor 13109 to allow for amplification and the processing of the acoustic signal.

When the laser signal is focused at a target area 13105, an acoustic wave can be produced from the target spot as a result of the mechanical stress induced by the electromagnetic field. The intensity of this acoustic signal depends on the intensity of the optical field at the target area.

This acoustic signal is used to monitor the quality of the focus at the target area 13105, and implemented as an optimization value for the systems and algorithms presented in embodiments 6, 7, 8, 9, 10 or 12. It is also used as the optimization value for the intensity at the subsurface target tissue area as an example in Embodiment 11.

During the laser-induced optical breakdown, the creation of a local plasma triggers the apparition of a Shockwave. Monitoring this Shockwave allows to observe if there has actually been a LIOB event, and to monitor its intensity.

A catheter includes, in addition to fiber 17, at least a transducer 13103, and electrical cable 13107. Embodiment 14: Observation system

Embodiment 14 includes the elements of any one of the embodiments previously presented, wherein an observation system 14111 is further included to monitor the location of the ablation 14115, and observe its effects (Figure 14(a)). The observation system can either be part of the catheter, or it can be used in conjunction, and not be part of the catheter.

The observation system 14111 can be, for example, (i) an Optical Coherence Tomography (OCT) system, (ii) an opto-accoustic system or (iii) a two-photon microscopy system.

OCT is an interferometric method where the interference between a reference beam, and the signal reflected from an area of a sample is observed. The length of the reference beam is changed, which results in the scanning in depth of the sample. The OCT is well suited for the observation of scattering media such as artery walls and structures, and since its contrast mechanism is based on the difference of index of refraction in the different parts of a sample, it is very well suited for the observation of the bubbles induced by the LIOB. An opto-acoustic observation method relies on observation of the acoustic signal triggered by an optical beam. The local heating of the sample due to light absorption triggers a local expansion, and results in ultrasonic pressure waves that travel through the surrounding area. An array of sensors is then used to monitor the location of the target area and the properties of the layers the pressure wave went through. The good penetration of acoustic wave in scattering media makes it an efficient imaging method in a turbid media.

The opto-acoustic system, as described in relation with previous embodiment 13, is also well suited to observation, firstly because the acoustic signal can be used as a beacon for focus optimization, as presented in embodiment 13, and secondly because it has a range of observation in depth which covers our objective of ablation depth. Two-photon microscopy is an observation method where we use the two-photon fluorescence or the second harmonic signal from a target 14115 as the signal to be observed. A scanning system allows us to reconstruct a complete image by point by point observation.

A two-photon system is well suited to complementary use with the presented ablation system, since the same high power laser used for LIOB ablation can also be used for two-photon microscopy (using lower power), and the signal can for example be collected via a high NA multi-mode fiber. The scanning system can either be the same as the one we use for ablation, or a separate one.

Having described now the preferred embodiments of this invention, it will be apparent to one of skill in the art that other embodiments incorporating its concept may be used. This invention should not be limited to the disclosed embodiments, but rather should be limited only by the scope of the appended claims.

Claims

1. Subsurface laser-induced optical breakdown (LIOB) ablation system (11) including:

- an optical source (13) for providing optical pulses;

an optical waveguide (17) for guiding the optical pulses to a subsurface target biological tissue site;

the system (11) being characterised in that it further includes:

- a pulse shaping system (15) configured to modify a temporal profile or a wavefront profile of an optical pulse provided by the optical source (13) to compensate for temporal or spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site, and to provide the compensated optical pulse to the optical waveguide (17) for guidance to the subsurface target biological tissue site.

2. System according to claim 1, wherein the pulse shaping system (15) is configured to modify a temporal profile or a wavefront profile of an optical pulse provided by the optical source (13) to compensate for temporal or spatial modifications imposed on the optical pulse during guiding of the optical pulse by the optical waveguide (17).

3. System (11) according to claim 1 or 2, wherein the pulse shaping system (15) is configured to modify a wavefront profile of an optical pulse provided by the optical source (13) to generate, at an output of the optical waveguide (17), an auto-focusing optical pulse that focuses to the subsurface target biological tissue site to induce ablation.

4. System (11) according to any previous claim, wherein the pulse shaping system (15) is configured to modify an optical pulse provided by the optical source (13) to generate a pulse having (i) a non-damaging first predetermined spatial energy distribution in the biological tissue at a first predetermined distance or surface preceding the subsurface target biological tissue site, and (ii) a second predetermined spatial energy distribution at the subsurface target biological tissue site inducing ablation.

5. System (11) according to claim 3 or 4, wherein the pulse shaping system (15) is configured to generate a pulse having a ring airy beam profile, a Bessel beam profile, a Pearcey beam profile or an accelerating parabolic beam profile at the output of the optical waveguide (17).

6. System (11) according to any one of the previous claims, comprising a holographic element (59, 739) to modify a wavefront profile of an optical pulse provided by the optical source (13) to compensate for spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site.

7. System (11) according to any previous claim, further including calculating means (47,965) for generating pulse modification data to be provided to wavefront modifying means (39;739;969) to modify the wavefront of the optical pulse provided by the optical source (13) or the holographic element (59, 739), and measurement means (51) for measuring a value representing the light intensity generated at the subsurface target tissue site by the optical pulse and for communicating said value to the calculating means (47).

8. System (11) according to any one of claims 1 or 2, further including calculating means (47, 965) for generating pulse modification data to be provided to wavefront modifying means (39,739,969) to modify the wavefront of the optical pulse provided by the optical source (13), and first measurement means (1199) for measuring a first value representing the light intensity generated at the subsurface target tissue site by the optical pulse and for communicating said first value to the calculating means (47, 965), and second measurement means (1199) for measuring a second value representing the light intensity generated by the optical pulse at a predetermined distance or at a surface preceding the target tissue site and for communicating said second value to the calculating means (47, 965).

9. System (11) according to the previous claim, wherein the calculating means (47, 965) is configured to receive said first and second values and to further generate pulse modification data, based on said received first and second values, in order to obtain a predetermined light intensity at the subsurface target tissue site permitting ablation and a predetermined light intensity at the predetermined distance or surface preceding the subsurface target tissue site that is lower than a predetermined damage threshold value.

10. System (11) according to the previous claim 8 or 9, wherein the first means (1199) for measuring a value representing the light intensity at the subsurface target tissue site includes means (13103, 13107, 13109) for measuring an acoustic signal intensity generated at the subsurface target tissue site, and the second means (1199) for measuring a value representing the light intensity at the tissue surface or at a predetermined distance above the subsurface target tissue site includes means for measuring alight signal intensity generated thereat.

11. System (11) according to any previous claim, wherein the pulse shaping system (15) is configured to modify a temporal profile or a wavefront profile of an optical pulse to compensate for modification of the pulse during passage through biological tissue to the subsurface target biological tissue site.

12. System (11) according to any one of previous claims 1 to 6 , wherein the system (11) further includes calculating means (47,965) for generating pulse modification data to be provided to wavefront modifying means (39,739,969) to modify the wavefront of the optical pulse provided by the optical source (13) or the holographic element (59, 739), and measurement means for measuring an optical intensity spatial distribution in a predetermined optical plane after the output of the fiber (17) and for communicating said value to the calculating means (47, 965), the calculating means (47,965) being further configured to calculate a correlation value for this measured optical intensity spatial distribution with a desired E-field spatial distribution at said predetermined optical plane .

13. System (11) according to any one of previous claims 1, 2, 7 or 11, wherein the pulse shaping system (15) is configured to modify a temporal profile or a wavefront profile of an optical pulse to maximize the optical light intensity generated by the optical pulse at the subsurface target tissue site.

14. System (11) according to any previous claim, further including at least one optical element (19) to focus the optical pulse exiting the optical waveguide (17) to the subsurface target tissue site, and the pulse shaping system (15) is configured to compensate for temporal or spatial modifications imposed on the optical pulse during the passage of the optical pulse through the at least one optical element (19).

15. System (11) according to claim 7, wherein the calculating means (47, 965) is configured to receive the value representing the light intensity at the target site and to further generate or provide pulse modification data, based on said received value, to adaptively maximize the light intensity generated at the subsurface target tissue site.

16. System (11) according to the previous claim 7 or 15, wherein the measurement means (51) for measuring a value representing the light intensity at the subsurface target tissue site includes means (103, 107, 109) for measuring an acoustic signal intensity or a light signal intensity generated at the subsurface target tissue site.

17. System (11) according to any previous claim, further including an observation system (111) for determining the location of an ablation site in the target tissue.

18. System (11) according to claim 1 or 2, wherein the pulse shaping system (15) is configured to modify a temporal profile of an optical pulse provided by the optical source (13) to compensate for temporal modifications imposed on the optical pulse during passage of the optical pulse through the optical waveguide (17), and the optical waveguide (17) is a single mode optical waveguide, and the system (11) further includes an additional pulse shaping system (12101) configured to modify a wavefront profile of the optical pulse outputted by the single mode waveguide (17) to compensate for spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site, said additional system (12101) being located to receive the pulse for treatment after passage of the optical pulse through the optical waveguide (17).

19. System (11) according to any previous claim, wherein the optical waveguide (17), or the optical waveguide (17) and the pulse shaping system (15), or the optical waveguide (17) and the at least one optical element (19), or the optical waveguide (17) and the pulse shaping system (15) as well as the at least one optical element (19) are included in a catheter.

20. System according to any one of the previous claims 1 to 17, wherein a pulse shaping system (Al, A2) is configured to modify a temporal profile and a wavefront profile of an optical pulse provided by the optical source (13) to compensate for temporal and spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site, and to provide the compensated optical pulse to the optical waveguide (17) for guidance to the subsurface target biological tissue site.

21. System according to any previous claim, wherein the pulse shaping system includes a grating (23) and a first spatial light modulator or a first digital micromirror device (25) to modify the temporal profile of the optical pulse by temporally delaying wavelength components of the optical pulse, and/or includes a second spatial light modulator or a second digital micromirror device (39) to modify the wavefront of the optical pulse by delaying parts of the wavefront of the optical pulse compared to a reference point of the wavefront.

22. Subsurface laser-induced optical breakdown (LIOB) ablation catheter including:

- an optical waveguide (17) for guiding optical pulses towards a subsurface target biological tissue site;

the catheter being characterised in that it further includes:

- a pulse shaping device (59; 1003; 12109) configured to modify a wavefront profile of an optical pulse provided to the catheter to compensate for spatial modifications imposed on the optical pulse during guidance or passage of the optical pulse to the subsurface target biological tissue site.

23. Subsurface laser-induced optical breakdown (LIOB) ablation method including the steps of: - providing an optical source (13) for producing optical pulses;

- providing an optical waveguide (17) for guiding the optical pulses to a subsurface target tissue site; the method being characterised by:

modifying a temporal profile or a wavefront profile of the optical pulse provided by the optical source (13) to compensate for temporal or spatial modifications imposed on the optical pulse during passage of the optical pulse to the subsurface target biological tissue site; and

- providing the compensated optical pulse to the optical waveguide (17) for guidance to the subsurface target biological tissue site.

24. Method according to claim 23, comprising modifying the temporal profile or the wavefront profile of the optical pulse provided by the optical source (13) to compensate for temporal or spatial modifications imposed on the optical pulse during guiding of the optical pulse by the optical waveguide (17).

25. Method according to claim 23 or 24, comprising modifying the wavefront profile of the optical pulse provided by the optical source (13) to generate, at an output of the optical waveguide, an auto-focusing optical pulse that focuses to the subsurface target biological tissue site to induce ablation.

26. Method according to any previous claim, comprising modifying the wavefront profile of the optical pulse provided by the optical source (13) to generate a pulse having (i) a non- ablation inducing first predetermined spatial energy distribution in the biological tissue at a first predetermined distance or surface preceding the subsurface target biological tissue site, and (ii) a second predetermined spatial energy distribution at the subsurface target biological tissue site inducing ablation.

27. Method according to claim 25 or 26, wherein the pulse generated is a pulse having a ring airy beam profile, a Bessel beam profile, a Pearcey beam profile or an accelerating parabolic beam profile.

28. Method according to any one of the previous claims, comprising providing a holographic element (59, 739) to modify a wavefront profile of an optical pulse provided by the optical source (13) to compensate for spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site.

29. Method according to any one of claims 23 to 28, further including the steps of generating pulse modification data and modifying the wavefront of the optical pulse provided by the optical source or the holographic element (59, 739) on the basis of said data, measuring a value representing a light intensity generated at the target ablation site by said modified optical pulse, and generating or providing further pulse modification data to optimize said measured value.

30. Method according to any one of previous claims 23 to 24 or 28 to 29, including the steps of generating pulse modification data and modifying the wavefront of the optical pulse provided by the optical source (13) based on said data, and measuring a first value representing a light intensity generated by the modified pulse at the subsurface target tissue site, and measuring a second value representing a light intensity generated by the modified pulse at a surface or location preceding the subsurface target tissue site.

31. Method according to the previous claim, including the step of comparing the measured first and second values to first and second threshold values, generating further pulse modification data if the first measured value is below the first threshold value and the second measured value is above the second threshold value, or using the pulse modification data to modifying the wavefront of the optical pulse provided by the optical source (13), based on said receive

32. Method according to any previous claim, comprising modifying a temporal profile or a wavefront profile of the optical pulse provided by the optical source (13) to compensate for modification of the pulse during passage through biological tissue to the subsurface target tissue site.

33. Method according to any one of previous claim 23 to 28, further including the steps of generating pulse modification data and modifying the wavefront of the optical pulse provided by the optical source or the holographic element (59, 739) on the basis of said data, and measuring a light intensity spatial distribution in an optical plane located along a pulse propagation direction at a predetermined distance after the output of the fiber (17) for generating or providing further pulse modification data to optimize a correlation value representing the correlation between said measured light intensity spatial distribution and a predetermined spatial distribution.

34. Method according to any one of previous claims 23 to 24 or 28 to 29, including modifying the wavefront profile of the optical pulse to maximize the light intensity generated by the optical pulse at the subsurface target tissue site.

35. Method according to any one of previous claims 23 to 34, including providing at least one optical element (19) to focus the optical pulse exiting the optical waveguide (17) at the subsurface target tissue site, and modifying a temporal profile or a wavefront profile of the optical pulse provided by the optical source (13) to compensate for modification imposed on the optical pulse during the passage of the optical pulse through the at least one optical element (19).

36. Method according to any one of previous claims 29 to 35, wherein an acoustic signal intensity or a light intensity signal generated at the subsurface target tissue site is measured.

37. Method according to any previous claim, further including the step of deternaming the location of an ablation site in the target tissue.

38. Method according to claim 23 or 24, including modifying a temporal profile of an optical pulse provided by the optical source (13) to compensate for temporal modifications imposed on the optical pulse during passage of the optical pulse through the optical waveguide (17), wherein the optical waveguide (17) is a single mode optical waveguide, and modifying a wavefront profile of the optical pulse outputted by the single mode waveguide (17) to compensate for spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site.

39. Method according to any one of previous claims 23 to 37, including modifying a temporal profile and a wavefront profile of an optical pulse provided by the optical source (13) to compensate for temporal and spatial modifications imposed on the optical pulse during the passage of the optical pulse to the subsurface target biological tissue site, and providing the compensated optical pulse to the optical waveguide (17) for guidance to the subsurface target biological tissue site.

40. Method according to any previous claim, including providing a grating and a first spatial light modulator or a first digital micromirror device to modify the temporal profile of the optical pulse by temporally delaying wavelength components of the optical pulse, and/or providing a second spatial light modulator or a second digital micromirror device to modify the wavefront of the optical pulse by delaying parts of the wavefront of the optical pulse compared to a reference point of the wavefront.